Biological Results and Discussion

The in-vitro inhibition activity of the synthesized target compounds against human mast cell tryptase is summarized in Tables 3.2.1 and 3.2.2 Compound 8, which contains aminomethyl benzyl moieties as head groups, was the most potent of the pyran series (type I), with a Ki value of 1.3 nM. Compared with 8, the tryptase inhibitors with aminomethylcyclohexyl substituents (17, 18, and 21), were 100-fold (Ki = 130 nM), 60-fold (Ki = 75 nM), and approximately 90-fold (Ki = 120 nM) less 

The most potent compound of the aryl diyne series (type II) was furan derivative 9 with a Ki value of 7.5 nM. An approximately tenfold decrease of potency was observed when the 1,3-substitution pattern of the head groups of 9 was replaced by 1,4-substitution to give 24 with a K, value of 80 nM. Substitution of the 2,5-furan ring in 9 by the 3,4-thiophene ring gave 25, with a twentyfold loss of tryptase inhibition activity (K, =150 nM). Replacement of the furanyl diyne template with the 1,3-substituted phenyl diyne template 29 was well tolerated (K, = 9 nM), whereas 1,4-substituted head groups resulted in a fourfold loss of activity (27, Ki = 32 nM) compared with 29. Combination of a 1,2-substituted phenyldiyne 

We have created efficient syntheses of remarkably potent and selective bifunctional tryptase inhibitors, which are also competitive and reversible, containing pyran moieties and hetero and non-hetero aryl diynes as scaffolds. Several modifications at the core templates and the linker moieties are well tolerated without significant loss of inhibition activity. In contrast with previous results published recently [32], it was also apparent from the aryl diyne inhibitors that the distance between the two terminal amino groups can be considerably less than 30 bonds in highly potent target compounds (e.g. 9 and 29 with 26 bonds each). The in-vitro potencies of the compounds were between 1 im for 26 and 1.3 nM for 15 with high selectivity against other serine proteases (trypsin, thrombin, and factor Xa, respectively) in 

Compel Tryptase [/imol] Trypsin [/imol] Thrombin [/imol] Factor Xa [/imol] 

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